The present invention relates to a process for the industrial synthesis of N-[(S)-1-carboxybutyl]-(S)-alanine esters, and to their application in the industrial synthesis of perindopril and its pharmaceutically acceptable salts.
More specifically, the present invention relates to a new process for the industrial synthesis of the compounds of formula (I): 
wherein R represents a linear or branched (C1-C6)alkyl group,
and addition salts thereof with a mineral or organic acid or base. The compounds of formula (I) obtained in accordance with the process of the invention are useful in the synthesis of perindopril of formula (II): 
and in the synthesis of pharmaceutically acceptable salts thereof.
Perindopril and salts thereof have valuable pharmacological properties. Their principal property lies in the inhibition of the enzyme that converts angiotensin I (or kininase II), which enables on the one hand prevention of the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (vasoconstrictor) and on the other hand prevention of the degradation of bradykinin (vasodilator) to inactive peptide. Those two actions contribute to the beneficial effects of perindopril in cardiovascular disorders, especially arterial hypertension and cardiac insufficiency.
Perindopril, its preparation and its therapeutic use have been described in European Patent Specification EP 0 049 658.
Given the pharmaceutical interest in that compound, it is important to be able to obtain the intermediate of formula (I) by an effective industrial synthesising process that allows especially the selective production of the (S,S) diastereoisomer in a good yield and with an excellent degree of purity but that can equally readily be performed on an industrial scale.
Some methods for the preparation of the compounds of formula (I) are already known, but on an industrial scale those processes have significant disadvantages:
The journal Tet. Lett. 1982, 23 (16), 1677-80 describes the production of a compound of formula (I) (R=ethyl) by reacting ethyl 2-oxovalerate with alanine tert-butyl ester in ethanol in the presence of sodium cyanoborohydride, but that reducing agent is particularly toxic, very hygroscopic and difficult to handle on an industrial scale.
The patent specification EP 0 309 324 describes obtaining a compound of formula (I) (R=ethyl) by reacting alanine benzyl ester with ethyl xcex1-bromovalerate in dimethylformamide in the presence of triethylamine. The major drawbacks of that process are the large number of steps involved and the low yield of the (S,S) isomer. Indeed, since the reaction is not diastereoselective, in order to obtain the pure (S,S) isomer it requires the addition of a purification step, which comprises fractional crystallisation in the presence of maleic acid.
The patent specifications EP 0 308 340 and EP 0 308 341 (equivalent to U.S. Pat. No. 4,914,214, the subject matter of which is hereby incorporated by reference) describe the production of a compound of formula (I) (R=ethyl) by reacting ethyl norvalinate hydrochloride with pyruvic acid in water in the presence of hydrogen, palladium-on-carbon and sodium hydroxide. The isolation of the crude product is then carried out by evaporation of the water, then ethanol is added to precipitate the sodium chloride formed during the reaction. After filtration, the ethanol solution obtained is evaporated and the residue is recrystallised from acetonitrile. That process has the advantage of resulting in a compound of formula (I) that has excellent optical purity: only the (S,S) diastereoisomer crystallises under those conditions. Furthermore, the use of pyruvic acid as reagent, a low-cost, industrially available, natural product, and the use of water as the reaction solvent, are particularly advantageous. On the other hand, however, a disadvantage of that process is that its use on an industrial scale is particularly laborious: the isolation of the reaction product is in fact effected by the evaporation of a large quantity of water and then requires a series of operations (addition of a first organic solvent, filtration, evaporation, and then recrystallisation from a second organic solvent) for the product to be obtained in chemically and optically pure form.
The Applicant has now developed a new process for the industrial synthesis of compounds of formula (I) that combines the advantages of hydrogenation in aqueous medium with a particularly rapid and simple isolation for use on an industrial scale.
More specifically, the present invention relates to a process for the industrial synthesis of compounds of formula (I) which is characterised in that sodium pyruvate of formula (III): 
is condensed with a compound of formula (IV): 
wherein R is as defined for formula (I),
with hydrogenation catalysed by 5% palladium-on-carbon,
in water,
at a pressure of from 1 to 20 bar, preferably from 1 to 5 bar,
at a temperature of from 10 to 60xc2x0 C., preferably from 10 to 40xc2x0 C.,
in the presence of sodium hydroxide in an amount of from 0.1 to 0.2 mol per mol of compound of formula (IV) used, in order to yield the compound of formula (I) directly, in optically pure form, following acidification of the reaction mixture to a pH of from 2.8 to 4.5, preferably from 3 to 3.5, and then filtration.
A low hydrogen pressure unexpectedly results in a yield and a chemical and enantiomeric purity that are as good as when the reaction is carried out at elevated pressure.
Surprisingly, the single precipitation after acidification of the aqueous reaction mixture yields the single (S,S) isomer with good chemical purity and excellent enantiomeric purity.
The recrystallisation step can thus be omitted, making the isolation particularly quick and simple to apply on an industrial scale.